Vaporizable alkaloid compositions and methods of use thereof

Abstract

In various embodiments of the present disclosure, vaporizable alkaloid compositions comprising a substituted pyridine compound of Formula (I) and entirely absent nicotine are described that are capable of forming an inhalable vapor when dispensed from an electronic device such as an e-cigarette. A series of such vaporizable alkaloid compositions having decreasing (w/v) amounts of substituted pyridine compound are provided as part of a smoking cessation program.

1 . A vaporizable alkaloid composition, comprising:
 at least one substituted pyridine compound of Formula (I):   
       
         
           
           
               
               
           
         
          or a salt, or mixed salt thereof, wherein:
 A is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and 
         
       
       
         
           
           
               
               
           
         
         
           R 6  and R 7  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6  and R 7  together are ═O; 
           R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; 
           R 13  and R 14  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13  and R 14  together are ═O; 
           n is an integer from 1 to 10; and 
           R 15  and R 16  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15  and R 16  together with the N atom to which they are bonded form a 3-8 membered optionally substituted heterocyclic ring, 
         
         with the proviso that if A is 
       
       
         
           
           
               
               
           
         
          and R 5  is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  cannot all be H; and 
         at least one solvent, 
         wherein the vaporizable alkaloid composition is entirely devoid of (R) or (S) nicotine. 
       
     
     
         2 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         3 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA-1): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         4 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA-2): 
       
         
           
           
               
               
           
         
       
       or mixed salt thereof. 
     
     
         5 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA-3): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         6 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA-4): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         7 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IA-5); 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         8 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IB): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         9 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IC): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         10 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (ID): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         11 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IE): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof. 
     
     
         12 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound has a structure according to Formula (IAA): 
       
         
           
           
               
               
           
         
       
       or a salt, or mixed salt thereof, with the proviso that if R 5  is CH 3 , then R 1 , R 2 , R 3 , and R 4  cannot all be H. 
     
     
         13 . The vaporizable alkaloid composition of  claim 1 , wherein the at least one substituted pyridine compound is selected from (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or(S)-2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt, or a mixed salt thereof. 
     
     
         14 . The vaporizable alkaloid composition of  claim 1 , further comprising an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methane sulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, tartronic acid, valeric acid, and mixtures thereof. 
     
     
         15 . The vaporizable alkaloid composition of  claim 14 , wherein the organic acid is selected from the group consisting of citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof. 
     
     
         16 . The vaporizable alkaloid composition of  claim 14 , wherein the molar ratio of total substituted pyridine compound to total organic acid is about 25:1 to about 75:1. 
     
     
         17 . The vaporizable alkaloid composition of  claim 1 , wherein the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof. 
     
     
         18 . The vaporizable alkaloid composition of  claim 1 , further comprising at least one chemosensory irritant. 
     
     
         19 . The vaporizable alkaloid composition of  claim 18 , wherein the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, icilin, polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidene malononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesyl thiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, cannabidiol, Δ 9 -tetrahydrocannabinol, baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol and mixtures thereof. 
     
     
         20 . The vaporizable alkaloid composition of  claim 18 , wherein the chemosensory irritant is a spice additive exhibiting a spiciness of from about 1,000 to about 20,000,000 Scoville Heat Units (SHU). 
     
     
         21 . The vaporizable alkaloid composition of  claim 20 , wherein the spice additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, Shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, piperanine (4,5-dihydropiperine), piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof. 
     
     
         22 . The vaporizable alkaloid composition of  claim 20 , wherein the spice additive is capsaicin or a mixture of capsaicinoids. 
     
     
         23 . A vaporizable alkaloid composition comprising:
 (a) from about 1 wt. % to about 80 wt. % of a substituted pyridine compound of Formula (I):   
       
         
           
           
               
               
           
         
          or a salt, or mixed salt thereof, wherein:
 A is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and 
         
       
       
         
           
           
               
               
           
         
         
           R 6  and R 7  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6  and R 7  together are ═O; 
           R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; 
           R 13  and R 14  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 3  and R 4  together are ═O; 
           n is an integer from 1 to 10; and 
           R 15  and R 16  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15  and R 16  together with the N atom to which they are bonded form a 3-8 membered optionally substituted heterocyclic ring, 
         
         with the proviso that if A is 
       
       
         
           
           
               
               
           
         
          and R 5  is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  cannot all be H; 
         (b) from about 0.05 wt. % to about 1.5 wt. % in total of at least one organic acid; and 
         (c) remainder solvent, 
         wherein the weight percentages are based on the total weight of the vaporizable alkaloid composition; and 
         wherein the molar ratio of moles of substituted pyridine compound to total moles of organic acid is from about 25:1 to about 75:1. 
       
     
     
         24 . The vaporizable alkaloid composition of  claim 23 , wherein the substituted pyridine compound is selected from nicotinamide, (S)-N,N-dimethyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-yl)propan-1-amine, (S)-N,N-dimethyl-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethan-1-amine, (S)-N,N-dimethyl-3-(2-(pyridin-3-yl)pyrrolidin-1-yl)propan-1-amine, N,N-dimethyl-1-(pyridin-3-yl)methanamine, and N-methyl-N-(pyridin-3-ylmethyl)ethanamine. 
     
     
         25 . The vaporizable composition of  claim 23 , wherein the molar ratio of moles substituted pyridine compound to total moles of organic acid is about 50:1. 
     
     
         26 . The vaporizable alkaloid composition of  claim 23 , wherein the at least one organic acid consists of a mixture of citric acid and acetic acid. 
     
     
         27 . The vaporizable alkaloid composition of  claim 23 , wherein the solvent is selected from the group consisting of propylene glycol, glycerin, ethanol, and mixtures thereof. 
     
     
         28 . The vaporizable alkaloid composition of  claim 23 , further comprising at least one chemosensory irritant. 
     
     
         29 . The vaporizable alkaloid composition of  claim 28 , wherein the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, icilin, polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidene malononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesyl thiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, cannabidiol, Δ 9 -tetrahydrocannabinol, baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol and mixtures thereof. 
     
     
         30 . The vaporizable alkaloid composition of  claim 28 , wherein the chemosensory irritant is a spice additive exhibiting a spiciness of from about 1,000 to about 20,000,000 Scoville Heat Units (SHU). 
     
     
         31 . The vaporizable alkaloid composition of  claim 30 , wherein the spice additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, Shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, piperanine (4,5-dihydropiperine), piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof. 
     
     
         32 . The vaporizable alkaloid composition of  claim 30 , wherein the spice additive is capsaicin or a mixture of capsaicinoids. 
     
     
         33 . A method for promoting smoking cessation in an individual desirous of cessation, the method comprising:
 administering to the individual, over a time period determined for cessation, a series of vaporizable alkaloid compositions for the individual to inhale by vaping, each vaporizable alkaloid composition in the series comprising at least one substituted pyridine compound according to Formula (I):   
       
         
           
           
               
               
           
         
          or a salt, or mixed salt thereof, wherein:
 A is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and 
         
       
       
         
           
           
               
               
           
         
         
           R 6  and R 7  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6  and R 7  together are ═O; 
           R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; 
           R 13  and R 14  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13  and R 14  together are ═O; 
           n is an integer from 1 to 10; and 
           R 15  and R 16  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15  and R 16  together with the N atom to which they are bonded form a 3-8 membered optionally substituted heterocyclic ring, 
         
         with the proviso that if A is 
       
       
         
           
           
               
               
           
         
          and R 5  is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  cannot all be H; 
         and at least one solvent; 
         wherein each of the vaporizable alkaloid compositions in the series of vaporizable alkaloid compositions comprises a decreasing (w/v) amount of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof; 
         wherein the series of vaporizable alkaloid compositions includes a vaporizable alkaloid composition having a highest (w/v) level of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof, and includes a vaporizable alkaloid composition having a lowest (w/v) level of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof; and 
         wherein the individual inhales by vaping each composition in the series beginning at a start of the time period determined for cessation with the vaporizable alkaloid composition having the highest level (w/v) of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof, and ending at an end of the time period determined for cessation with the composition having the lowest level (w/v) of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof, such that at commencement of the time period determined for cessation the individual ceases smoking. 
       
     
     
         34 . The method of  claim 33 , wherein the vaporizable alkaloid composition in the series of vaporizable alkaloid compositions having the highest level (w/v) of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof comprises about 100 mg/mL of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof. 
     
     
         35 . The method of  claim 33 , wherein the vaporizable alkaloid composition in the series of vaporizable alkaloid compositions having the lowest level (w/v) of substituted pyridine compound of Formula (I), or salt, or mixed salt thereof comprises no more than about 1 mg/mL of said substituted pyridine compound of Formula (I), or salt, or mixed salt thereof. 
     
     
         36 . The method of  claim 33 , wherein the time period determined for cessation is part of a smoking cessation program that further includes dispensation of the series of vaporizable alkaloid compositions to the individual desirous of cessation over the time period determined for cessation.